Polycystic kidney disease (PKD) is a genetically inherited disease and one of the leading causes of end-stage renal disease. PKD can be characterized by the presence of multiple, fluid-filled cysts in one or both kidneys, resulting in massive enlargement of the kidneys. Disease progression can lead to reduction in renal function and eventual kidney failure can require dialysis and possible kidney transplantation in up to 50% of patients. Autosomal dominant PKD (ADPKD) is the most commonly inherited form of the disease that can affect about 1 in 400 to 1 in 1000 people worldwide. ADPKD typically progresses to end-stage renal disease in the 4th to 6th decades of life. Additional clinical manifestations of ADPKD can include hypertension, back and side pain, cerebral aneurysms, hepatic cysts, pancreatic cysts, cardiac valve disease (especially mitral valve prolapse), urinary tract infections, hematuria, kidney stones, colonic diverticula, and aortic root dilatation. Most prescribed treatments address specific manifestations of PKD and do not address underlying causes of the disease and/or have not been proven to prevent or delay decline of renal function. For example, over-the-counter pain medications (e.g., NSAIDs, acetaminophen) or prescribed narcotics or other pain medications are used to control pain symptoms, and anti-hypertensive medications are prescribed to control blood pressure.
The sympathetic nervous system (SNS) is a primarily involuntary bodily control system typically associated with stress responses. Fibers of the SNS extend through tissue in almost every organ system of the human body and can affect characteristics such as pupil diameter, gut motility, and urinary output. Such regulation can have adaptive utility in maintaining homeostasis or in preparing the body for rapid response to environmental factors. Chronic activation of the SNS, however, is a common maladaptive response that can drive the progression of many disease states. Excessive activation of the renal SNS in particular has been identified experimentally and in humans as a likely contributor to the complex pathophysiology of hypertension, states of volume overload (such as heart failure), and progressive renal disease. As examples, radiotracer dilution has demonstrated increased renal norepinephrine (NE) spillover rates in patients with essential hypertension, and elevated sympathetic nervous system activity has been shown to be present in ADPKD.
Sympathetic nerves of the kidneys terminate in the blood vessels, the juxtaglomerular apparatus, and the renal tubules. Stimulation of the renal sympathetic nerves can cause increased renin release, increased sodium (Na+) reabsorption, and a reduction of renal blood flow. These neural regulation components of renal function are considerably stimulated in disease states characterized by heightened sympathetic tone as well as likely contribute to increased blood pressure in hypertensive patients. The reduction of renal blood flow and glomerular filtration rate as a result of renal sympathetic efferent stimulation is likely a cornerstone of the loss of renal function in cardio-renal syndrome (i.e., renal dysfunction as a progressive complication of chronic heart failure). Pharmacologic strategies to thwart the consequences of renal efferent sympathetic stimulation include centrally acting sympatholytic drugs, beta blockers (intended to reduce renin release), angiotensin converting enzyme inhibitors and receptor blockers (intended to block the action of angiotensin II calcium channel blockers and vasodilators (to counteract peripheral vasoconstriction caused by increased sympathetic drive), aldosterone blockers (to block the actions of increased aldosterone released from activation of the renin-angiotensin-aldosterone system), and aldosterone activation consequent to renin release), and diuretics (intended to counter the renal sympathetic mediated sodium and water retention). These pharmacologic strategies, however, have significant limitations including limited efficacy, compliance issues, side effects, and others.